This is a revised competing, continuation application for studies on the role of cocaine in the immunopathogenesis of HIV-1 infection that was first funded in 1999. In the present application, we propose to build on this earlier work and move forward. The current application focuses on novel, dendritic cell (DC) based immunotherapeutic strategies against susceptibility to and progression of HIV infections in drug using, HIV-1 infected populations. Blood monocyte derived DC are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. They play a critical role in harboring HIV and possibly infecting T cells and/or modulating T cell immune responses. Cocaine is one of the most widely abused drugs in the U.S. and the last decade has witnessed a great, entangled epidemic of cocaine abuse and HIV-1 infections. Although previous studies, including our own, have shown that cocaine exerts significant immunomodulatory activities on lymphocyte subpopulations, the effects of drug abuse on dendritic cell activities that lead to disease progression in the drug-using population with or without HIV infection has not been examined. Consequently, the following hypothesis will be tested by the proposed experiments: cocaine is a cofactor in the pathogenesis of HIV infections by acting in synergy with certain HIV proteins on dendritic cell functions subsequently leading to dysregulation of the immune system of the infected host. Further, we propose that cocaine mediates these effects on DC through several mechanisms including: 1) down regulating the expression of various costimulatory molecules and proinflammatory cytokines/chemokines (that are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation), 2) upregulating indolamine 2,3 dioxygenase (IDO) that is known to suppress T cell immune functions, and 3) upregulating the DC-specific, CD4 independent virus attachment receptor, DC-SIGN and its homolog DC-SIGNR that is active on DC. Further, we shall determine the mechanism(s) of cocaine- mediated dysregulation of DC functions by examining signal transduction and use of siRNA and cocaine specific receptor inhibition studies. Our preliminary studies show that cocaine significantly downregulates costimulatory molecules with a reciprocal upregulation of DC-SIGN and IDO and these effects appears to be mediated via dysregulation of MAPKs. Data will be stratified on the basis of HIV disease status, CD4 counts, HIV viral load and cocaine use. These studies may lead to novel anti-HIV therapies such as targeting the CD4 independent, virus attachment receptor, DC-SIGN, or devising inhibitors of TDO and DC-SIGN or stimulating costimulatory molecules.